E2F1/CKS2/PTEN signaling axis regulates malignant phenotypes in pediatric retinoblastoma

Abstract

Retinoblastoma (RB) is the most common pediatric intraocular malignancy and is a serious vision- and life-threatening disease. The biallelic mutation of the retinoblastoma gene RB1 is the initial event in the malignant transformation of RB, but the exact molecular mechanism is still unclear. E2F transcription factors can be activated by RB1 loss of function and lead to uncontrolled cell division. Among E2F family numbers, E2F1 has higher expression abundance than E2F2 and E2F3 in RB clinical samples. By integrating E2F1 ChIP-seq data, RNA-seq profiling from RB samples and RNA-seq profiling upon E2F1 knockdown, together with pathway analysis, literature searching and experimental validation, we identified Cyclin-dependent kinases regulatory subunit 2 (CKS2) as a novel regulator in regulating tumor-associated phenotypes in RB. CKS2 exhibited aberrantly higher expression in RB. Depletion of CKS2 in Y79 retinoblastoma cell line led to reduced cell proliferation, delayed DNA replication and decreased clonogenic growth. Downregulation of CKS2 also slowed tumor xenograft growth in nude mice. Importantly, reversed expression of CKS2 rescued cancer-associated phenotypes. Mechanistically, transcription factor E2F1 enhanced CKS2 expression through binding to its promoter and CKS2 regulated the cancer-associated PI3K–AKT pathway. This study discovered E2F1/CKS2/PTEN signaling axis regulates malignant phenotypes in pediatric retinoblastoma, and CKS2 may serve as a potential therapeutic target for this disease.

N6‐methyladenosine methyltransferase METTL3 modulates the cell cycle of granulosa cells via CCND1 and AURKB in Haimen goats

“…TRRUST analysis 23 and WB results indicated that METTL3 interference had a direct impact on the RB‐E2Fs complex, rather than affecting the p53‐p21‐RB‐E2Fs signaling pathway. It is commonly known that when RB is hypophosphorylated, it binds to E2Fs transcription factor dimers and represses the transcription activities of E2Fs 41,42 . Our results suggested that loss of METTL3 function resulted in the suppression of E2Fs, which is achieved by diminishing the p‐RB in goat granulosa cells.…”

“…It is commonly known that when RB is hypophosphorylated, it binds to E2Fs transcription factor dimers and represses the transcription activities of E2Fs. 41,42 Our results suggested that loss of METTL3 function resulted in the suppression of E2Fs, which is achieved by diminishing the p-RB in goat granulosa cells. Among the RB-E2Fs target genes, many code for key cell cycle regulators such as AURKB, 43 and we also found that E2F1 inhibition downregulated the expression of AURKB in goat granulosa cells.…”

Heterogeneity of cancer-associated fibroblasts in head and neck squamous cell carcinoma

“…Our study incorporated data from TCGA and revealed that only CKS2+ iCAFs exhibited significant prognostic relevance ( P <0.05). CKS2 protein binds to the catalytic subunit of cyclin-dependent kinases, thereby activating their biological functions [ 41 , 42 ]. Gene Ontology (GO) annotations associated with CKS2 include cyclin-dependent protein serine/threonine kinase regulator activity.…”

Development and validation of potential molecular subtypes and signatures of thyroid carcinoma based on aging-related gene analysis

“…E2F1 activates transcription and is essential for regulating the cell cycle, apoptosis, and proliferation by targeting DNA promoters [39]. E2F1 has recently been implicated in numerous tumor types, including breast cancer [40] and retinoblastoma [41]. Interleukin-6 (IL-6) is remarkably active in immunity, in ammation, and metabolism [42].…”